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Promiscuous targeting of bromodomains by bromosporine (BSP)
Bromodomains (BRDs) have emerged as compelling targets for cancer therapy, however the complex multidomain/subunit architecture of BRD-protein complexes complicates predictions of consequences of their pharmacological targeting. To address this, we developed a promiscuous bromodomain inhibitor (bromosporine, BSP) that broadly targets BRDs with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle we chose to test BSP in leukemias, where currently 6 registered clinical trials seek to target bromo and extra-terminal (BET) BRDs. Using cell line models we systematically demonstrate that bromosporine simulates a phenotype that is phenocopied by BET inhibition. Bromosporine therefore represents a unique, extremely well characterized chemotype, capable of accessing the effect of poly-bromodomain inhibition, to establish proof of principle linking acetylation-dependent readout to disease phenotypes.
PMID: 27757418
Science Advances: http://advances.sciencemag.org/content/2/10/e1600760